Literature Review

Clinical question: What is the cost and frequency of ED revisits within three days and 30 days?

Background: ED revisits lead to a financial and resource utilization burden on the medical system. The costs and rates of these return visits are unknown and limited in characterization.

Study design: Observational study.

Setting: Six states, using Healthcare Cost and Utilization Project databases.

Synopsis: An observational study examined data from 2006-2010 across six states to determine cost and frequency of ED revisits within a 30-day period from initial ED treatment and discharge. The study examined revisit rates within the first three days of discharge, as well as the 30 days following discharge from the initial presentation.

Three-day revisit rates were 8.2%, with 29% resulting in admission; 32% of the revisits took place at a different institution.

The 30-day revisit rate was 19.9%, with 28% resulting in admission. The most common diagnoses were skin and soft tissue infections (23.9%) and abdominal pain (9.7%). The vast majority of revisits (89%) resulted in the same diagnosis as the first encounter.

Cost of the revisits was more difficult to assess, because only one of six states had full data (Florida); the cost data was extrapolated for the other states involved. In Florida, three-day revisit costs accounted for 30.3% of all primary visit costs. Thirty-day revisit costs were 118% of all primary ED visits costs within that time period.

There was not always an indication of whether the revisit was due to a planned revisit, worsening of symptoms, or inadequate initial treatment, however, leaving the evaluation of cost and revisit burden incomplete.

Bottom line: Initial evaluation of ED revisits shows that rates and cost are significant, though the nature of the revisits remains underevaluated. Preliminary data demonstrate that ED revisits are a significant cost to the healthcare system, though the number of preventable revisits remains unknown.

Citation: Duseja R, Bardach NS, Lin GA, et al. Revisit rates and associated costs after and emergency department encounter. Ann Intern Med. 2015;162(11):750-756.

Clinical question: What is the cost and frequency of ED revisits within three days and 30 days?

Background: ED revisits lead to a financial and resource utilization burden on the medical system. The costs and rates of these return visits are unknown and limited in characterization.

Study design: Observational study.

Setting: Six states, using Healthcare Cost and Utilization Project databases.

Synopsis: An observational study examined data from 2006-2010 across six states to determine cost and frequency of ED revisits within a 30-day period from initial ED treatment and discharge. The study examined revisit rates within the first three days of discharge, as well as the 30 days following discharge from the initial presentation.

Three-day revisit rates were 8.2%, with 29% resulting in admission; 32% of the revisits took place at a different institution.

The 30-day revisit rate was 19.9%, with 28% resulting in admission. The most common diagnoses were skin and soft tissue infections (23.9%) and abdominal pain (9.7%). The vast majority of revisits (89%) resulted in the same diagnosis as the first encounter.

Cost of the revisits was more difficult to assess, because only one of six states had full data (Florida); the cost data was extrapolated for the other states involved. In Florida, three-day revisit costs accounted for 30.3% of all primary visit costs. Thirty-day revisit costs were 118% of all primary ED visits costs within that time period.

There was not always an indication of whether the revisit was due to a planned revisit, worsening of symptoms, or inadequate initial treatment, however, leaving the evaluation of cost and revisit burden incomplete.

Bottom line: Initial evaluation of ED revisits shows that rates and cost are significant, though the nature of the revisits remains underevaluated. Preliminary data demonstrate that ED revisits are a significant cost to the healthcare system, though the number of preventable revisits remains unknown.

Citation: Duseja R, Bardach NS, Lin GA, et al. Revisit rates and associated costs after and emergency department encounter. Ann Intern Med. 2015;162(11):750-756.

Clinical question: What is the cost and frequency of ED revisits within three days and 30 days?

Background: ED revisits lead to a financial and resource utilization burden on the medical system. The costs and rates of these return visits are unknown and limited in characterization.

Study design: Observational study.

Setting: Six states, using Healthcare Cost and Utilization Project databases.

Synopsis: An observational study examined data from 2006-2010 across six states to determine cost and frequency of ED revisits within a 30-day period from initial ED treatment and discharge. The study examined revisit rates within the first three days of discharge, as well as the 30 days following discharge from the initial presentation.

Three-day revisit rates were 8.2%, with 29% resulting in admission; 32% of the revisits took place at a different institution.

The 30-day revisit rate was 19.9%, with 28% resulting in admission. The most common diagnoses were skin and soft tissue infections (23.9%) and abdominal pain (9.7%). The vast majority of revisits (89%) resulted in the same diagnosis as the first encounter.

Cost of the revisits was more difficult to assess, because only one of six states had full data (Florida); the cost data was extrapolated for the other states involved. In Florida, three-day revisit costs accounted for 30.3% of all primary visit costs. Thirty-day revisit costs were 118% of all primary ED visits costs within that time period.

There was not always an indication of whether the revisit was due to a planned revisit, worsening of symptoms, or inadequate initial treatment, however, leaving the evaluation of cost and revisit burden incomplete.

Bottom line: Initial evaluation of ED revisits shows that rates and cost are significant, though the nature of the revisits remains underevaluated. Preliminary data demonstrate that ED revisits are a significant cost to the healthcare system, though the number of preventable revisits remains unknown.

Citation: Duseja R, Bardach NS, Lin GA, et al. Revisit rates and associated costs after and emergency department encounter. Ann Intern Med. 2015;162(11):750-756.

Clinical question: What are the differences between factors associated with early (zero to seven days after discharge) and late (eight to 30 days after discharge) readmission?

Background: Thirty-day readmission rates are a quality metric; however, recent evidence challenges the notion that readmissions represent unnecessary and preventable healthcare use. It remains unclear whether the 30-day window post-discharge represents a homogenous period or if there are factors that contribute to readmission during that time.

Study design: Retrospective, single-center, cohort study.

Setting: Large, urban teaching hospital.

Synopsis: Based on 13,355 admissions representing 8,078 patients over a two-year period, the overall readmission rate was 19.7%, with 7.8% early (zero to seven days post-discharge) readmissions, and 11.9% late (eight to 30 days post-discharge) readmissions. Variables were categorized as indicators of acute illness burden, chronic illness burden, patient care process factors, and social determinants of health.

Several markers of acute illness burden were associated with early readmission only. Some markers of chronic illness burden were associated with late readmissions only (e.g. hemodialysis), while others were associated with readmissions throughout the 30-day period. Worse social determinants of health increased odds of readmission in both periods.

The single-center study was able to examine detailed clinical variables; however, this approach limited the generalizability of the the results.

Bottom line: Policies to reduce 30-day readmissions should reflect the different risk factors at play across that time frame.

Citation: Graham KL, Wilker EH, Howell MD, Davis RB, Marcantonio ER. Differences between early and late readmissions among patients: A cohort study. Ann Intern Med. 2015;162(11):741-749.

Clinical question: What are the differences between factors associated with early (zero to seven days after discharge) and late (eight to 30 days after discharge) readmission?

Background: Thirty-day readmission rates are a quality metric; however, recent evidence challenges the notion that readmissions represent unnecessary and preventable healthcare use. It remains unclear whether the 30-day window post-discharge represents a homogenous period or if there are factors that contribute to readmission during that time.

Study design: Retrospective, single-center, cohort study.

Setting: Large, urban teaching hospital.

Synopsis: Based on 13,355 admissions representing 8,078 patients over a two-year period, the overall readmission rate was 19.7%, with 7.8% early (zero to seven days post-discharge) readmissions, and 11.9% late (eight to 30 days post-discharge) readmissions. Variables were categorized as indicators of acute illness burden, chronic illness burden, patient care process factors, and social determinants of health.

Several markers of acute illness burden were associated with early readmission only. Some markers of chronic illness burden were associated with late readmissions only (e.g. hemodialysis), while others were associated with readmissions throughout the 30-day period. Worse social determinants of health increased odds of readmission in both periods.

The single-center study was able to examine detailed clinical variables; however, this approach limited the generalizability of the the results.

Bottom line: Policies to reduce 30-day readmissions should reflect the different risk factors at play across that time frame.

Citation: Graham KL, Wilker EH, Howell MD, Davis RB, Marcantonio ER. Differences between early and late readmissions among patients: A cohort study. Ann Intern Med. 2015;162(11):741-749.

Clinical question: What are the differences between factors associated with early (zero to seven days after discharge) and late (eight to 30 days after discharge) readmission?

Background: Thirty-day readmission rates are a quality metric; however, recent evidence challenges the notion that readmissions represent unnecessary and preventable healthcare use. It remains unclear whether the 30-day window post-discharge represents a homogenous period or if there are factors that contribute to readmission during that time.

Study design: Retrospective, single-center, cohort study.

Setting: Large, urban teaching hospital.

Synopsis: Based on 13,355 admissions representing 8,078 patients over a two-year period, the overall readmission rate was 19.7%, with 7.8% early (zero to seven days post-discharge) readmissions, and 11.9% late (eight to 30 days post-discharge) readmissions. Variables were categorized as indicators of acute illness burden, chronic illness burden, patient care process factors, and social determinants of health.

Several markers of acute illness burden were associated with early readmission only. Some markers of chronic illness burden were associated with late readmissions only (e.g. hemodialysis), while others were associated with readmissions throughout the 30-day period. Worse social determinants of health increased odds of readmission in both periods.

The single-center study was able to examine detailed clinical variables; however, this approach limited the generalizability of the the results.

Bottom line: Policies to reduce 30-day readmissions should reflect the different risk factors at play across that time frame.

Citation: Graham KL, Wilker EH, Howell MD, Davis RB, Marcantonio ER. Differences between early and late readmissions among patients: A cohort study. Ann Intern Med. 2015;162(11):741-749.

Clinical question: How can patient adherence to pharmacological thromboprophylaxis be improved?

Background: Prior studies suggest that the hospital-wide prevalence of nonadministration of VTE thromboprophylaxis orders ranges from 5% to 13%, with patient refusal listed as the most common reason for nonadministration.

Study design: Quasi-experimental, pre-post intervention, with intervention and control units.

Setting: Academic medical center in Philadelphia.

Synopsis: Researchers identified 20,208 admissions for the study; 8,293 (41%) admissions occurred prior to the intervention and 11,915 (59%) after. The three-part intervention, which was composed of (1) standardized nurse response to patient refusal, (2) integration of daily assessment of VTE into rounds, and (3) regular audit with feedback, resulted in a decrease in nonadministration rates during the intervention. Rates continued to decline in the 21-month follow-up period.

After the intervention, the rate of missed doses of pharmacological thromboprophylaxis decreased from 24.7% to 14.7% (P<0.01). This was due to a decrease in patient refusal from 18.3% to 9.4% (P<0.01).

Although there was a decrease in the missed doses of thromboprophylaxis, there was no statistically significant change in the rate of hospital-associated VTE.

Bottom line: A multifaceted intervention resulted in a decrease in the proportion of missed and refused doses of pharmacological VTE thromboprophylaxis, but this was not associated with a statistically significant change in VTE rates.

Citation: Baillie CA, Guevara JP, Boston RC, Hecht TE. A unit-based intervention aimed at improving patient adherence to pharmacological thromboprophylaxis [published online ahead of print June 2, 2015]. BMJ Qual Saf. doi:10.1136/bmjqs-2015-003992.

Clinical question: How can patient adherence to pharmacological thromboprophylaxis be improved?

Background: Prior studies suggest that the hospital-wide prevalence of nonadministration of VTE thromboprophylaxis orders ranges from 5% to 13%, with patient refusal listed as the most common reason for nonadministration.

Study design: Quasi-experimental, pre-post intervention, with intervention and control units.

Setting: Academic medical center in Philadelphia.

Synopsis: Researchers identified 20,208 admissions for the study; 8,293 (41%) admissions occurred prior to the intervention and 11,915 (59%) after. The three-part intervention, which was composed of (1) standardized nurse response to patient refusal, (2) integration of daily assessment of VTE into rounds, and (3) regular audit with feedback, resulted in a decrease in nonadministration rates during the intervention. Rates continued to decline in the 21-month follow-up period.

After the intervention, the rate of missed doses of pharmacological thromboprophylaxis decreased from 24.7% to 14.7% (P<0.01). This was due to a decrease in patient refusal from 18.3% to 9.4% (P<0.01).

Although there was a decrease in the missed doses of thromboprophylaxis, there was no statistically significant change in the rate of hospital-associated VTE.

Bottom line: A multifaceted intervention resulted in a decrease in the proportion of missed and refused doses of pharmacological VTE thromboprophylaxis, but this was not associated with a statistically significant change in VTE rates.

Citation: Baillie CA, Guevara JP, Boston RC, Hecht TE. A unit-based intervention aimed at improving patient adherence to pharmacological thromboprophylaxis [published online ahead of print June 2, 2015]. BMJ Qual Saf. doi:10.1136/bmjqs-2015-003992.

Clinical question: How can patient adherence to pharmacological thromboprophylaxis be improved?

Background: Prior studies suggest that the hospital-wide prevalence of nonadministration of VTE thromboprophylaxis orders ranges from 5% to 13%, with patient refusal listed as the most common reason for nonadministration.

Study design: Quasi-experimental, pre-post intervention, with intervention and control units.

Setting: Academic medical center in Philadelphia.

Synopsis: Researchers identified 20,208 admissions for the study; 8,293 (41%) admissions occurred prior to the intervention and 11,915 (59%) after. The three-part intervention, which was composed of (1) standardized nurse response to patient refusal, (2) integration of daily assessment of VTE into rounds, and (3) regular audit with feedback, resulted in a decrease in nonadministration rates during the intervention. Rates continued to decline in the 21-month follow-up period.

After the intervention, the rate of missed doses of pharmacological thromboprophylaxis decreased from 24.7% to 14.7% (P<0.01). This was due to a decrease in patient refusal from 18.3% to 9.4% (P<0.01).

Although there was a decrease in the missed doses of thromboprophylaxis, there was no statistically significant change in the rate of hospital-associated VTE.

Bottom line: A multifaceted intervention resulted in a decrease in the proportion of missed and refused doses of pharmacological VTE thromboprophylaxis, but this was not associated with a statistically significant change in VTE rates.

Citation: Baillie CA, Guevara JP, Boston RC, Hecht TE. A unit-based intervention aimed at improving patient adherence to pharmacological thromboprophylaxis [published online ahead of print June 2, 2015]. BMJ Qual Saf. doi:10.1136/bmjqs-2015-003992.

Clinical question: Is there a score that will predict the mortality rate in elderly patients presenting with a non-ST-elevation myocardial infarction (NSTEMI)?

Background: Although they represent only 9% of patients in clinical trials, patients over the age of 75 make up one third of patients with NSTEMI, accounting for more than half of NSTEMI-related mortality.

Study design: Retrospective cohort analysis for score calculator design, with prospective cohort validation.

Setting: The retrospective cohort was derived from a meta-analysis of 55 papers. The prospective validation arm used a cohort of patients from a randomized multicenter Italian trial.

Synopsis: The authors developed and validated a mortality predictor for patients 75 and older who present with an NSTEMI. The calculator: hemoglobin less than 10 g/dl (two points), elevated troponin levels, ECG ischemic changes, estimated glomerular filtration rate (eGFR) less than 45, previous vascular event (one point each two). The calculator predicted probabilities of death in one year ranging from 2% (score of zero) to 75% (score of six). The calculator allowed stratification into low (score: zero to one), intermediate (score: two), or high (score: three or greater) risk. High-risk patients appeared to benefit from intervention with significantly reduced risk for mortality (odds ratio 0.44).

Bottom line: A simple risk calculator stratifies elderly patients into low, intermediate, or high risk to predict mortality from NSTEMI. High-risk patients appear to achieve a mortality benefit from intervention.

Citation: Angeli F, Cavallini C, Verdecchia P, et al. A risk score for predicting 1-year mortality in patients ≥75 years of age presenting with non-ST-elevation acute coronary syndrome. Am J Cardiol. 2015;116(2):208-213.

Clinical question: Is there a score that will predict the mortality rate in elderly patients presenting with a non-ST-elevation myocardial infarction (NSTEMI)?

Background: Although they represent only 9% of patients in clinical trials, patients over the age of 75 make up one third of patients with NSTEMI, accounting for more than half of NSTEMI-related mortality.

Study design: Retrospective cohort analysis for score calculator design, with prospective cohort validation.

Setting: The retrospective cohort was derived from a meta-analysis of 55 papers. The prospective validation arm used a cohort of patients from a randomized multicenter Italian trial.

Synopsis: The authors developed and validated a mortality predictor for patients 75 and older who present with an NSTEMI. The calculator: hemoglobin less than 10 g/dl (two points), elevated troponin levels, ECG ischemic changes, estimated glomerular filtration rate (eGFR) less than 45, previous vascular event (one point each two). The calculator predicted probabilities of death in one year ranging from 2% (score of zero) to 75% (score of six). The calculator allowed stratification into low (score: zero to one), intermediate (score: two), or high (score: three or greater) risk. High-risk patients appeared to benefit from intervention with significantly reduced risk for mortality (odds ratio 0.44).

Bottom line: A simple risk calculator stratifies elderly patients into low, intermediate, or high risk to predict mortality from NSTEMI. High-risk patients appear to achieve a mortality benefit from intervention.

Citation: Angeli F, Cavallini C, Verdecchia P, et al. A risk score for predicting 1-year mortality in patients ≥75 years of age presenting with non-ST-elevation acute coronary syndrome. Am J Cardiol. 2015;116(2):208-213.

Clinical question: Is there a score that will predict the mortality rate in elderly patients presenting with a non-ST-elevation myocardial infarction (NSTEMI)?

Background: Although they represent only 9% of patients in clinical trials, patients over the age of 75 make up one third of patients with NSTEMI, accounting for more than half of NSTEMI-related mortality.

Study design: Retrospective cohort analysis for score calculator design, with prospective cohort validation.

Setting: The retrospective cohort was derived from a meta-analysis of 55 papers. The prospective validation arm used a cohort of patients from a randomized multicenter Italian trial.

Synopsis: The authors developed and validated a mortality predictor for patients 75 and older who present with an NSTEMI. The calculator: hemoglobin less than 10 g/dl (two points), elevated troponin levels, ECG ischemic changes, estimated glomerular filtration rate (eGFR) less than 45, previous vascular event (one point each two). The calculator predicted probabilities of death in one year ranging from 2% (score of zero) to 75% (score of six). The calculator allowed stratification into low (score: zero to one), intermediate (score: two), or high (score: three or greater) risk. High-risk patients appeared to benefit from intervention with significantly reduced risk for mortality (odds ratio 0.44).

Bottom line: A simple risk calculator stratifies elderly patients into low, intermediate, or high risk to predict mortality from NSTEMI. High-risk patients appear to achieve a mortality benefit from intervention.

Citation: Angeli F, Cavallini C, Verdecchia P, et al. A risk score for predicting 1-year mortality in patients ≥75 years of age presenting with non-ST-elevation acute coronary syndrome. Am J Cardiol. 2015;116(2):208-213.

Among current smokers, migraine may increase the risk of stroke and combined vascular events, according to research published online ahead of print July 22 in Neurology. Migraine may not be associated with these outcomes among nonsmokers, however.

Teshamae S. Monteith, MD, Assistant Professor of Clinical Neurology at University of Miami School of Medicine, and colleagues found that study participants with migraine had twice the risk of silent brain infarctions, but they considered the findings to be consistent with previous data that suggest that migraine is not a significant risk factor for stroke among older subjects. “We thought that factors associated with a greater migraine burden, such as obesity, might put migraineurs more at risk of vascular events, but this was not the case,” said Dr. Monteith.

Cohort Was Ethnically Diverse
Data have suggested that migraine with aura is an independent risk factor for ischemic stroke in women younger than 45. Migraine also has been associated with an unfavorable cardiovascular risk profile. Dr. Monteith and colleagues initiated their study to assess the association between migraine with and without aura and stroke. They examined data from the prospective Northern Manhattan Study, which enrolled an ethnically diverse, older, community-based cohort.

Eligible participants were stroke-free, older than 40, and had lived in northern Manhattan for three months or longer. Dr. Monteith’s group excluded participants with a history of meningitis, head trauma, or radiation to rule out individuals with the potential for secondary headache. They also excluded people with a myocardial infarction before baseline.

Bilingual research assistants collected data through interviews in English or Spanish. Baseline data included demographics, socioeconomic factors, medical history and medication use, vascular risk factors, family history, and migraine history. The investigators adapted standard questions regarding hypertension, diabetes, cigarette smoking, and cardiac conditions using the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. Self-reported migraine was assessed with a questionnaire, and additional questions closely adhered to the International Classification of Headache Disorders, second edition criteria for migraine.

Study participants were screened annually by phone for changes in clinical status, and patients who screened positive were invited for an interview and examination by a neurologist. The primary outcome was adjudicated stroke. The secondary outcomes were confirmed combined vascular events (ie, stroke, myocardial infarction, or vascular death), myocardial infarction, and vascular death.

Migraine Tripled Smokers’ Stroke Risk
The researchers had information on migraine status for 1,292 participants. Among this population, 262 participants had migraine (75 with aura, 187 without aura). People with migraine were younger and more likely to be women and have Medicaid or no insurance and several vascular risk factors. Over a mean follow-up of 11 years, the researchers observed 294 combined vascular events, including 114 strokes, 94 myocardial infarctions, and 178 vascular deaths.

Migraine was not associated with risk of combined vascular events including stroke or stroke-only outcomes. When they examined migraine with aura and migraine without aura separately, the investigators found no associations in relation to combined vascular events including stroke or to stroke alone. Age at baseline, sex, race or ethnicity, smoking, moderate alcohol use, moderate to heavy physical activity, BMI, hypertension, hypercholesterolemia, or diabetes did not modify the effect.

The researchers did, however, observe an interaction between current smoking and stroke. They also found an interaction between current smoking and combined vascular events. A stratified analysis yielded a hazard ratio of stroke for migraine versus no migraine among current smokers of 3.17. Among former smokers, the hazard ratio was 0.87, and among participants who had never smoked, the hazard ratio was 0.49 when controlling for socioeconomic and vascular risk factors.

Mechanism of Increased Risk Is Unclear
Previous research has indicated that migraine with aura is an independent risk factor of recurrent ischemic stroke and other vascular events in young patients with ischemic stroke. In addition, stroke risk associated with migraine with aura was greater in younger than in older women in the Women’s Health Study. “Perhaps our participants were too old to display such a relationship between migraine with aura and stroke in both men and women of postmenopausal age,” said Dr. Monteith.

Oxidative stress may be the mechanism by which migraine increases stroke risk among smokers. Oxidative stress may have a role in migraine and may increase susceptibility to vascular events among active smokers. Furthermore, prothrombotic states, decreased platelet hemostasis time, and endothelial dysfunction, which are associated with migraine, are plausible mechanisms that may enhance stroke risk in active smokers. “We suspect that a synergic action may occur between vascular changes of migraine and smoking as an effect modifier, although further work is necessary to elucidate this association,” said Dr. Monteith.

The data appear to suggest that vascular changes in migraine are an important subclinical vascular marker for stroke and combined vascular events among active smokers. Because smoking may be common among migraineurs, the authors recommended that smoking cessation counseling be encouraged as a part of routine migraine care throughout the patient’s lifetime. “The identification of modifiable vascular risk factors and treatments may have beneficial outcomes for stroke reduction in the elderly population with migraine,” they concluded.

—Erik Greb

Among current smokers, migraine may increase the risk of stroke and combined vascular events, according to research published online ahead of print July 22 in Neurology. Migraine may not be associated with these outcomes among nonsmokers, however.

Teshamae S. Monteith, MD, Assistant Professor of Clinical Neurology at University of Miami School of Medicine, and colleagues found that study participants with migraine had twice the risk of silent brain infarctions, but they considered the findings to be consistent with previous data that suggest that migraine is not a significant risk factor for stroke among older subjects. “We thought that factors associated with a greater migraine burden, such as obesity, might put migraineurs more at risk of vascular events, but this was not the case,” said Dr. Monteith.

Cohort Was Ethnically Diverse
Data have suggested that migraine with aura is an independent risk factor for ischemic stroke in women younger than 45. Migraine also has been associated with an unfavorable cardiovascular risk profile. Dr. Monteith and colleagues initiated their study to assess the association between migraine with and without aura and stroke. They examined data from the prospective Northern Manhattan Study, which enrolled an ethnically diverse, older, community-based cohort.

Eligible participants were stroke-free, older than 40, and had lived in northern Manhattan for three months or longer. Dr. Monteith’s group excluded participants with a history of meningitis, head trauma, or radiation to rule out individuals with the potential for secondary headache. They also excluded people with a myocardial infarction before baseline.

Bilingual research assistants collected data through interviews in English or Spanish. Baseline data included demographics, socioeconomic factors, medical history and medication use, vascular risk factors, family history, and migraine history. The investigators adapted standard questions regarding hypertension, diabetes, cigarette smoking, and cardiac conditions using the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. Self-reported migraine was assessed with a questionnaire, and additional questions closely adhered to the International Classification of Headache Disorders, second edition criteria for migraine.

Study participants were screened annually by phone for changes in clinical status, and patients who screened positive were invited for an interview and examination by a neurologist. The primary outcome was adjudicated stroke. The secondary outcomes were confirmed combined vascular events (ie, stroke, myocardial infarction, or vascular death), myocardial infarction, and vascular death.

Migraine Tripled Smokers’ Stroke Risk
The researchers had information on migraine status for 1,292 participants. Among this population, 262 participants had migraine (75 with aura, 187 without aura). People with migraine were younger and more likely to be women and have Medicaid or no insurance and several vascular risk factors. Over a mean follow-up of 11 years, the researchers observed 294 combined vascular events, including 114 strokes, 94 myocardial infarctions, and 178 vascular deaths.

Migraine was not associated with risk of combined vascular events including stroke or stroke-only outcomes. When they examined migraine with aura and migraine without aura separately, the investigators found no associations in relation to combined vascular events including stroke or to stroke alone. Age at baseline, sex, race or ethnicity, smoking, moderate alcohol use, moderate to heavy physical activity, BMI, hypertension, hypercholesterolemia, or diabetes did not modify the effect.

The researchers did, however, observe an interaction between current smoking and stroke. They also found an interaction between current smoking and combined vascular events. A stratified analysis yielded a hazard ratio of stroke for migraine versus no migraine among current smokers of 3.17. Among former smokers, the hazard ratio was 0.87, and among participants who had never smoked, the hazard ratio was 0.49 when controlling for socioeconomic and vascular risk factors.

Mechanism of Increased Risk Is Unclear
Previous research has indicated that migraine with aura is an independent risk factor of recurrent ischemic stroke and other vascular events in young patients with ischemic stroke. In addition, stroke risk associated with migraine with aura was greater in younger than in older women in the Women’s Health Study. “Perhaps our participants were too old to display such a relationship between migraine with aura and stroke in both men and women of postmenopausal age,” said Dr. Monteith.

Oxidative stress may be the mechanism by which migraine increases stroke risk among smokers. Oxidative stress may have a role in migraine and may increase susceptibility to vascular events among active smokers. Furthermore, prothrombotic states, decreased platelet hemostasis time, and endothelial dysfunction, which are associated with migraine, are plausible mechanisms that may enhance stroke risk in active smokers. “We suspect that a synergic action may occur between vascular changes of migraine and smoking as an effect modifier, although further work is necessary to elucidate this association,” said Dr. Monteith.

The data appear to suggest that vascular changes in migraine are an important subclinical vascular marker for stroke and combined vascular events among active smokers. Because smoking may be common among migraineurs, the authors recommended that smoking cessation counseling be encouraged as a part of routine migraine care throughout the patient’s lifetime. “The identification of modifiable vascular risk factors and treatments may have beneficial outcomes for stroke reduction in the elderly population with migraine,” they concluded.

—Erik Greb

Among current smokers, migraine may increase the risk of stroke and combined vascular events, according to research published online ahead of print July 22 in Neurology. Migraine may not be associated with these outcomes among nonsmokers, however.

Teshamae S. Monteith, MD, Assistant Professor of Clinical Neurology at University of Miami School of Medicine, and colleagues found that study participants with migraine had twice the risk of silent brain infarctions, but they considered the findings to be consistent with previous data that suggest that migraine is not a significant risk factor for stroke among older subjects. “We thought that factors associated with a greater migraine burden, such as obesity, might put migraineurs more at risk of vascular events, but this was not the case,” said Dr. Monteith.

Cohort Was Ethnically Diverse
Data have suggested that migraine with aura is an independent risk factor for ischemic stroke in women younger than 45. Migraine also has been associated with an unfavorable cardiovascular risk profile. Dr. Monteith and colleagues initiated their study to assess the association between migraine with and without aura and stroke. They examined data from the prospective Northern Manhattan Study, which enrolled an ethnically diverse, older, community-based cohort.

Eligible participants were stroke-free, older than 40, and had lived in northern Manhattan for three months or longer. Dr. Monteith’s group excluded participants with a history of meningitis, head trauma, or radiation to rule out individuals with the potential for secondary headache. They also excluded people with a myocardial infarction before baseline.

Bilingual research assistants collected data through interviews in English or Spanish. Baseline data included demographics, socioeconomic factors, medical history and medication use, vascular risk factors, family history, and migraine history. The investigators adapted standard questions regarding hypertension, diabetes, cigarette smoking, and cardiac conditions using the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. Self-reported migraine was assessed with a questionnaire, and additional questions closely adhered to the International Classification of Headache Disorders, second edition criteria for migraine.

Study participants were screened annually by phone for changes in clinical status, and patients who screened positive were invited for an interview and examination by a neurologist. The primary outcome was adjudicated stroke. The secondary outcomes were confirmed combined vascular events (ie, stroke, myocardial infarction, or vascular death), myocardial infarction, and vascular death.

Migraine Tripled Smokers’ Stroke Risk
The researchers had information on migraine status for 1,292 participants. Among this population, 262 participants had migraine (75 with aura, 187 without aura). People with migraine were younger and more likely to be women and have Medicaid or no insurance and several vascular risk factors. Over a mean follow-up of 11 years, the researchers observed 294 combined vascular events, including 114 strokes, 94 myocardial infarctions, and 178 vascular deaths.

Migraine was not associated with risk of combined vascular events including stroke or stroke-only outcomes. When they examined migraine with aura and migraine without aura separately, the investigators found no associations in relation to combined vascular events including stroke or to stroke alone. Age at baseline, sex, race or ethnicity, smoking, moderate alcohol use, moderate to heavy physical activity, BMI, hypertension, hypercholesterolemia, or diabetes did not modify the effect.

The researchers did, however, observe an interaction between current smoking and stroke. They also found an interaction between current smoking and combined vascular events. A stratified analysis yielded a hazard ratio of stroke for migraine versus no migraine among current smokers of 3.17. Among former smokers, the hazard ratio was 0.87, and among participants who had never smoked, the hazard ratio was 0.49 when controlling for socioeconomic and vascular risk factors.

Mechanism of Increased Risk Is Unclear
Previous research has indicated that migraine with aura is an independent risk factor of recurrent ischemic stroke and other vascular events in young patients with ischemic stroke. In addition, stroke risk associated with migraine with aura was greater in younger than in older women in the Women’s Health Study. “Perhaps our participants were too old to display such a relationship between migraine with aura and stroke in both men and women of postmenopausal age,” said Dr. Monteith.

Oxidative stress may be the mechanism by which migraine increases stroke risk among smokers. Oxidative stress may have a role in migraine and may increase susceptibility to vascular events among active smokers. Furthermore, prothrombotic states, decreased platelet hemostasis time, and endothelial dysfunction, which are associated with migraine, are plausible mechanisms that may enhance stroke risk in active smokers. “We suspect that a synergic action may occur between vascular changes of migraine and smoking as an effect modifier, although further work is necessary to elucidate this association,” said Dr. Monteith.

The data appear to suggest that vascular changes in migraine are an important subclinical vascular marker for stroke and combined vascular events among active smokers. Because smoking may be common among migraineurs, the authors recommended that smoking cessation counseling be encouraged as a part of routine migraine care throughout the patient’s lifetime. “The identification of modifiable vascular risk factors and treatments may have beneficial outcomes for stroke reduction in the elderly population with migraine,” they concluded.

—Erik Greb

Peripheral plasma levels of the CNS protein tau are chronically elevated after traumatic brain injury (TBI) and appear to correlate with the severity of postconcussive symptoms, according to a report published online ahead of print August 3 in JAMA Neurology.

If these findings are confirmed, tau may be the first biomarker that is sensitive and specific to persistent TBI-related symptoms. The results also suggest that “months to years after the primary brain injury, there may be a continuation of secondary injuries with residual axonal degeneration and blood–brain barrier disruptions in this population that may contribute to the maintenance of postconcussive disorder symptoms and affect symptom severity,” said Anlys Olivera, PhD, of the National Institute of Nursing Research in Bethesda, Maryland, and her associates.

Tau stabilizes the structure of the axonal cytoskeleton. It is elevated in the CSF and the peripheral blood (albeit in extremely low concentrations) of patients with severe TBI, professional boxers, and athletes who sustain concussions. The extremely low levels of tau in the peripheral blood have been difficult to measure until the recent development of an ultrahigh-sensitivity immunoassay technology. Using this innovation, the researchers were able to examine for the first time the associations between plasma tau levels and the frequency and severity of deployment-related TBIs.

Over a two-year period, Dr. Olivera and her associates assessed tau levels in 70 members of the military who self-reported one or more TBIs and 28 military control subjects without TBI who were matched for age, sex, race, time since deployment, and number of deployments. Almost all participants in the TBI group had been injured at least 18 months previously. The most common causes of TBI were blows to the head, exposure to blasts, vehicular crashes, and sports-related concussions.

Total tau was significantly increased in the TBI group (mean level, 1.13 pg/mL), compared with the control group (0.63 pg/mL). Total tau also increased with increasing severity of the initial brain injury, with increasing number of TBIs, and with increasing severity of present-day postconcussive symptoms. These associations, moreover, were independent of symptoms of post-traumatic stress disorder and depression, which were prevalent in the TBI group, the investigators said.

Tau is not only a marker of brain injury, it also can contribute to secondary injury processes such as inflammation, which makes it a potential target for therapy. If the findings of this study are confirmed and extended to demonstrate a direct mechanistic relationship between TBI and tau aggregation, treatments such as the direct delivery of proteasomes “would be invaluable, considering the dearth of treatments for TBIs and chronic [postconcussive disorder] symptoms,” Dr. Olivera and her associates said.

Among the study limitations cited by the investigators are lack of neuroimaging and neuropsychologic data.

—Mary Ann Moon

Peripheral plasma levels of the CNS protein tau are chronically elevated after traumatic brain injury (TBI) and appear to correlate with the severity of postconcussive symptoms, according to a report published online ahead of print August 3 in JAMA Neurology.

If these findings are confirmed, tau may be the first biomarker that is sensitive and specific to persistent TBI-related symptoms. The results also suggest that “months to years after the primary brain injury, there may be a continuation of secondary injuries with residual axonal degeneration and blood–brain barrier disruptions in this population that may contribute to the maintenance of postconcussive disorder symptoms and affect symptom severity,” said Anlys Olivera, PhD, of the National Institute of Nursing Research in Bethesda, Maryland, and her associates.

Tau stabilizes the structure of the axonal cytoskeleton. It is elevated in the CSF and the peripheral blood (albeit in extremely low concentrations) of patients with severe TBI, professional boxers, and athletes who sustain concussions. The extremely low levels of tau in the peripheral blood have been difficult to measure until the recent development of an ultrahigh-sensitivity immunoassay technology. Using this innovation, the researchers were able to examine for the first time the associations between plasma tau levels and the frequency and severity of deployment-related TBIs.

Over a two-year period, Dr. Olivera and her associates assessed tau levels in 70 members of the military who self-reported one or more TBIs and 28 military control subjects without TBI who were matched for age, sex, race, time since deployment, and number of deployments. Almost all participants in the TBI group had been injured at least 18 months previously. The most common causes of TBI were blows to the head, exposure to blasts, vehicular crashes, and sports-related concussions.

Total tau was significantly increased in the TBI group (mean level, 1.13 pg/mL), compared with the control group (0.63 pg/mL). Total tau also increased with increasing severity of the initial brain injury, with increasing number of TBIs, and with increasing severity of present-day postconcussive symptoms. These associations, moreover, were independent of symptoms of post-traumatic stress disorder and depression, which were prevalent in the TBI group, the investigators said.

Tau is not only a marker of brain injury, it also can contribute to secondary injury processes such as inflammation, which makes it a potential target for therapy. If the findings of this study are confirmed and extended to demonstrate a direct mechanistic relationship between TBI and tau aggregation, treatments such as the direct delivery of proteasomes “would be invaluable, considering the dearth of treatments for TBIs and chronic [postconcussive disorder] symptoms,” Dr. Olivera and her associates said.

Among the study limitations cited by the investigators are lack of neuroimaging and neuropsychologic data.

—Mary Ann Moon

Peripheral plasma levels of the CNS protein tau are chronically elevated after traumatic brain injury (TBI) and appear to correlate with the severity of postconcussive symptoms, according to a report published online ahead of print August 3 in JAMA Neurology.

If these findings are confirmed, tau may be the first biomarker that is sensitive and specific to persistent TBI-related symptoms. The results also suggest that “months to years after the primary brain injury, there may be a continuation of secondary injuries with residual axonal degeneration and blood–brain barrier disruptions in this population that may contribute to the maintenance of postconcussive disorder symptoms and affect symptom severity,” said Anlys Olivera, PhD, of the National Institute of Nursing Research in Bethesda, Maryland, and her associates.

Tau stabilizes the structure of the axonal cytoskeleton. It is elevated in the CSF and the peripheral blood (albeit in extremely low concentrations) of patients with severe TBI, professional boxers, and athletes who sustain concussions. The extremely low levels of tau in the peripheral blood have been difficult to measure until the recent development of an ultrahigh-sensitivity immunoassay technology. Using this innovation, the researchers were able to examine for the first time the associations between plasma tau levels and the frequency and severity of deployment-related TBIs.

Over a two-year period, Dr. Olivera and her associates assessed tau levels in 70 members of the military who self-reported one or more TBIs and 28 military control subjects without TBI who were matched for age, sex, race, time since deployment, and number of deployments. Almost all participants in the TBI group had been injured at least 18 months previously. The most common causes of TBI were blows to the head, exposure to blasts, vehicular crashes, and sports-related concussions.

Total tau was significantly increased in the TBI group (mean level, 1.13 pg/mL), compared with the control group (0.63 pg/mL). Total tau also increased with increasing severity of the initial brain injury, with increasing number of TBIs, and with increasing severity of present-day postconcussive symptoms. These associations, moreover, were independent of symptoms of post-traumatic stress disorder and depression, which were prevalent in the TBI group, the investigators said.

Tau is not only a marker of brain injury, it also can contribute to secondary injury processes such as inflammation, which makes it a potential target for therapy. If the findings of this study are confirmed and extended to demonstrate a direct mechanistic relationship between TBI and tau aggregation, treatments such as the direct delivery of proteasomes “would be invaluable, considering the dearth of treatments for TBIs and chronic [postconcussive disorder] symptoms,” Dr. Olivera and her associates said.

Among the study limitations cited by the investigators are lack of neuroimaging and neuropsychologic data.

—Mary Ann Moon

An elevated rate of autism traits was seen among a cohort of children exposed to antiepileptic drugs (AEDs) in utero. Study findings were reported in the July Epilepsia. “The most important determinant of association with autistic traits was higher doses of sodium valproate exposure,” said Amanda G. Wood, PhD, MPsych, a Senior Lecturer in the School of Psychology at the University of Birmingham in the United Kingdom.

While the use of valproate in women who may become pregnant is generally avoided, there are insufficient data regarding the risk of autism spectrum disorders with low-dose valproate. “If this risk is no greater than with other AEDs, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child,” Dr. Wood said.

Dr. Wood and colleagues conducted a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. Participants were 105 Australian children ages 6 to 8 who were recruited through the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS).

Among the cohort, 11 children (10.5%) had elevated CARS scores, and this proportion was substantially higher than the estimated prevalence of autism spectrum disorders in age-matched children nationally or internationally. Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal IQ, and socioeconomic status.

Children who had in utero exposure to valproate were most likely to have elevated CARS scores, with 7.7% of the valproate monotherapy group and 46.7% of the valproate polytherapy group displaying autism spectrum disorder symptoms. The dose of valproate taken during pregnancy was found to be an independent risk factor for elevated CARS scores, whereas polytherapy was not. “CARS scores were not elevated in children exposed to polytherapy without valproate, suggesting that valproate, or valproate dose, rather than polytherapy per se, is the critical determinant of the relationship,” the researchers said.

—Glenn S. Williams

An elevated rate of autism traits was seen among a cohort of children exposed to antiepileptic drugs (AEDs) in utero. Study findings were reported in the July Epilepsia. “The most important determinant of association with autistic traits was higher doses of sodium valproate exposure,” said Amanda G. Wood, PhD, MPsych, a Senior Lecturer in the School of Psychology at the University of Birmingham in the United Kingdom.

While the use of valproate in women who may become pregnant is generally avoided, there are insufficient data regarding the risk of autism spectrum disorders with low-dose valproate. “If this risk is no greater than with other AEDs, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child,” Dr. Wood said.

Dr. Wood and colleagues conducted a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. Participants were 105 Australian children ages 6 to 8 who were recruited through the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS).

Among the cohort, 11 children (10.5%) had elevated CARS scores, and this proportion was substantially higher than the estimated prevalence of autism spectrum disorders in age-matched children nationally or internationally. Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal IQ, and socioeconomic status.

Children who had in utero exposure to valproate were most likely to have elevated CARS scores, with 7.7% of the valproate monotherapy group and 46.7% of the valproate polytherapy group displaying autism spectrum disorder symptoms. The dose of valproate taken during pregnancy was found to be an independent risk factor for elevated CARS scores, whereas polytherapy was not. “CARS scores were not elevated in children exposed to polytherapy without valproate, suggesting that valproate, or valproate dose, rather than polytherapy per se, is the critical determinant of the relationship,” the researchers said.

—Glenn S. Williams

An elevated rate of autism traits was seen among a cohort of children exposed to antiepileptic drugs (AEDs) in utero. Study findings were reported in the July Epilepsia. “The most important determinant of association with autistic traits was higher doses of sodium valproate exposure,” said Amanda G. Wood, PhD, MPsych, a Senior Lecturer in the School of Psychology at the University of Birmingham in the United Kingdom.

While the use of valproate in women who may become pregnant is generally avoided, there are insufficient data regarding the risk of autism spectrum disorders with low-dose valproate. “If this risk is no greater than with other AEDs, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child,” Dr. Wood said.

Dr. Wood and colleagues conducted a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. Participants were 105 Australian children ages 6 to 8 who were recruited through the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS).

Among the cohort, 11 children (10.5%) had elevated CARS scores, and this proportion was substantially higher than the estimated prevalence of autism spectrum disorders in age-matched children nationally or internationally. Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal IQ, and socioeconomic status.

Children who had in utero exposure to valproate were most likely to have elevated CARS scores, with 7.7% of the valproate monotherapy group and 46.7% of the valproate polytherapy group displaying autism spectrum disorder symptoms. The dose of valproate taken during pregnancy was found to be an independent risk factor for elevated CARS scores, whereas polytherapy was not. “CARS scores were not elevated in children exposed to polytherapy without valproate, suggesting that valproate, or valproate dose, rather than polytherapy per se, is the critical determinant of the relationship,” the researchers said.

—Glenn S. Williams